ACTIVELLE

8-2901-23-081-5

The format of this leaflet was determined by the Ministry of

Health and its content was checked and approved in June 2016

PATIENT PACKAGE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) – 1986

This medicine is dispensed with a doctor’s

prescription only

Activelle®

Film-coated tablets

The active ingredients are: Estradiol 1 mg/

norethisterone acetate 0.5 mg

Inactive ingredients in the preparation:

see section 6 - Further information.

Read all of this leaflet carefully before you start taking

this medicine. This leaflet contains concise information

about the medicine. If you have any further questions, ask

your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

This medicine has been prescribed for you only. Do not

pass it on to others. It may harm them, even if their signs

of illness are the same as yours.

If you get any side effects, talk to your doctor or

pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

What is this medicine intended for?

Before using the medicine

How to use the medicine?

Side effects

How to store the medicine?

Further information

1. What is this medicine intended for?

Activelle® is a continuous combined Hormone Replacement

Therapy (HRT). It contains two types of female hormones, an

oestrogen and a progestagen. Activelle® is suitable for

postmenopausal women with at least 1 year since their last

natural period.

Activelle® is used for:

Relief of symptoms occurring after menopause

During the menopause, the amount of oestrogen produced by

a woman’s body drops. This can cause symptoms such as hot

face, neck and chest (‘hot flushes’). Activelle® alleviates these

symptoms after menopause. You will only be prescribed

Activelle® if your symptoms seriously hinder your daily life.

Prevention of osteoporosis

After the menopause some women may develop fragile bones

(osteoporosis).

You should discuss all available options with your doctor.

If you are at an increased risk of fractures due to osteoporosis

and other medicines are not suitable for you, you can use

Activelle® to prevent osteoporosis after menopause.

Activelle® is prescribed for women who have not had their womb

removed, and whose periods stopped more than a year ago.

There is only limited experience of treating women older than

65 years with Activelle®.

Therapeutic group: Progestagens and oestrogens.

2. Before using the medicine

Medical history and regular check-ups

The use of HRT carries risks which need to be considered when

deciding whether to start taking it, or whether to carry on

taking it.

The experience in treating women with a premature

menopause (due to ovarian failure or surgery) is limited. If you

have a premature menopause the risks of using HRT may be

different. Please talk to your doctor.

Before you start (or restart) HRT, your doctor will ask about

your own and your family’s medical history. Your doctor may

decide to perform a physical examination. This may include an

examination of your breasts and/or an internal examination, if

necessary.

Once you have started on Activelle® you should see your

doctor for regular check-ups (at least once a year). At these

check-ups, discuss with your doctor the benefits and risks of

continuing with Activelle®.

Go for regular breast screening, as recommended by your doctor.

Do not take the medicine

if any of the following applies to you. If you are not sure about

any of the points below, talk to your doctor before taking

Activelle®.

Do not take Activelle®:

If you are allergic (hypersensitive) to estradiol,

norethisterone acetate or any of the other ingredients of

Activelle® (listed in section 6 ‘Further information’).

If you have, have had or suspect having breast cancer.

If you have, or have had cancer which is sensitive to

oestrogens, such as cancer of the womb lining

(endometrium), or if you are suspected of having it.

If you have any unexplained vaginal bleeding.

If you have excessive thickening of the womb lining

(endometrial hyperplasia) that is not being treated.

If you have or have ever had a blood clot in a vein

(thrombosis), such as in the legs (deep venous thrombosis)

or the lungs (pulmonary embolism).

If you have a blood clotting disorder (such as protein C,

protein S or antithrombin deficiency).

If you have or previously have had a disease caused by blood

clots in the arteries, such as a heart attack, stroke or angina.

If you have or have ever had a liver disease and your liver

function tests have not returned to normal.

If you have a rare blood problem called ‘porphyria’

which is passed down in families (inherited).

If any of the above conditions appear for the first time while

taking Activelle®, stop taking it at once and consult your

doctor immediately.

Special warnings regarding the use of this medicine

Before treatment with Activelle®, tell your doctor if you

have ever had any of the following problems, before you start

the treatment, as these may return or become worse during

treatment with Activelle®. If so, you should see your doctor

more often for check-ups:

fibroids inside your womb

growth of the womb lining outside your womb

(endometriosis) or a history of excessive growth of the

womb lining (endometrial hyperplasia)

increased risk of developing blood clots (see ‘Blood clots in

a vein (thrombosis)’)

increased risk of getting an oestrogen-sensitive cancer

(such as having a mother, sister or grandmother who has

had breast cancer)

high blood pressure

a liver disorder, such as a benign liver tumour

diabetes

gallstones

migraine or severe headaches

a disease of the immune system that affects many organs

of the body (systemic lupus erythematosus, SLE)

epilepsy

asthma

a disease affecting the eardrum and hearing (otosclerosis)

a very high level of fat in your blood (triglycerides)

fluid retention due to cardiac or kidney problems

lactose intolerance.

Stop taking Activelle® and see a doctor immediately

If you notice any of the following when taking HRT:

any of the conditions mentioned in the ‘Do not take the

medicine’ section

yellowing of your skin or the whites of your eyes

(jaundice). These may be signs of a liver disease

a large rise in your blood pressure (symptoms may be

headache, tiredness, dizziness)

migraine-like headaches which happen for the first time

if you become pregnant

if you notice signs of a blood clot, such as:

– painful swelling and redness of the legs

– sudden chest pain

– difficulty in breathing.

For more information, see ‘Blood clots in a vein (thrombosis)’.

Note: Activelle® is not a contraceptive. If it is less than

12 months since your last menstrual period or you are under

50 years old, you may still need to use additional contraception

to prevent pregnancy. Speak to your doctor for advice.

HRT and cancer

Excessive thickening of the lining of the womb

(endometrial hyperplasia) and cancer of the lining of the

womb (endometrial cancer)

Taking oestrogen-only HRT will increase the risk of excessive

thickening of the lining of the womb (endometrial hyperplasia)

and cancer of the womb lining (endometrial cancer).

The progestagen in Activelle® protects you from this extra risk.

Irregular bleeding

You may have irregular bleeding or drops of blood (spotting)

during the first 3-6 months of taking Activelle®.

However, if the irregular bleeding:

carries on for more than the first 6 months

starts after you have been taking Activelle® for more than

6 months

carries on after you have stopped taking Activelle®

see your doctor as soon as possible.

Breast cancer

Evidence suggests that taking combined oestrogen-

progestagen and possibly also oestrogen-only HRT increases

the risk of breast cancer. The extra risk depends on how long

you take HRT. The additional risk becomes clear within a few

years. However, it returns to normal within a few years

(at most 5) after stopping treatment.

Compare

Women aged 50 to 79 who are not taking HRT, on average,

9 to 17 in 1,000 will be diagnosed with breast cancer over

a 5-year period.

For women aged 50 to 79 who are taking oestrogen-

progestagen HRT over 5 years, there will be 13 to 23 cases in

1,000 users (i.e. an extra 4 to 6 cases).

Regularly check your breasts. See your doctor if you

notice any changes such as:

dimpling of the skin

changes in the nipple

any lumps you can see or feel.

Additionally, you are advised to join mammography screening

programs when offered to you. For mammogram screening, it

is important that you inform the nurse/healthcare professional

who is actually taking the x-ray that you use HRT, as this

medication may increase the density of your breasts which may

affect the outcome of the mammogram. Where the density of

the breast is increased, mammography may not detect all lumps.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. The use

of oestrogen-only or combined oestrogen-progestagen HRT has

been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in

women aged 50 to 54 who are not taking HRT, about

2 women in 2,000 will be diagnosed with ovarian cancer over

a 5-year period. For women who have been taking HRT for

5 years, there will be about 3 cases per 2,000 users (i.e. about

1 extra case).

Effect of HRT on heart and circulation

Blood clots in a vein (thrombosis)

The risk of blood clots in the veins is about 1.3 to 3 times

higher in HRT users than in non-users, especially during the

first year of taking it.

Blood clots can be serious, and if one travels to the lungs, it

can cause chest pain, breathlessness, fainting or even death.

You are more likely to get a blood clot in your veins as you get

older and if any of the following applies to you. Inform your

doctor if any of these situations applies to you:

you are unable to walk for a long time because of major

surgery, injury or illness (see also section 3, ‘If you need to

have surgery’)

you are seriously overweight (BMI >30 kg/m

you have any blood clotting problem that needs long-term

treatment with a medicine used to prevent blood clots

if any of your close relatives has ever had a blood clot in

the leg, lung or another organ

you have systemic lupus erythematosus (SLE)

you have cancer.

For signs of a blood clot, see ‘Stop taking Activelle® and see

a doctor immediately’.

Compare

Looking at women in their 50s who are not taking HRT, on

average, over a 5-year period, 4 to 7 in 1,000 would be

expected to get a blood clot in a vein.

For women in their 50s who have been taking oestrogen-

progestagen HRT for over 5 years, there will be 9 to 12 cases in

1,000 users (i.e. an extra 5 cases).

Heart disease (heart attack)

There is no evidence that HRT will prevent a heart attack.

Women over the age of 60 years who use oestrogen-

progestagen HRT are slightly more likely to develop heart

disease than those not taking any HRT.

Stroke

The risk of getting a stroke is about 1.5 times higher in HRT

users than in non-users. The number of extra cases of stroke

due to use of HRT will increase with age.

Compare

Looking at women in their 50s who are not taking HRT, on

average, 8 in 1,000 would be expected to have a stroke over

a 5-year period.

For women in their 50s who are taking HRT, there will be

11 cases in 1,000 users over 5 years (i.e. an extra 3 cases).

Other conditions

HRT will not prevent memory loss. There is some evidence of

a higher risk of memory loss in women who start using HRT

after the age of 65. Speak to your doctor for advice.

Other medicines and Activelle®

If you are taking or if you have recently taken other

medicines, including non-prescription

medicines, nutritional supplements, herbal medicines or

other natural products, tell the doctor or pharmacist.

Some medicines may interfere with the effect of Activelle®.

This might lead to irregular bleeding. This applies to the

following medicines:

Medicines for epilepsy (such as phenobarbital, phenytoin

and carbamazepine)

Medicines for tuberculosis (such as rifampicin and rifabutin)

Medicines for HIV infections (such as nevirapine,

efavirenz, ritonavir and nelfinavir)

Herbal remedies containing St John’s Wort (Hypericum

perforatum)

Medicines for hepatitis C infections (such as telaprevir).

Other medicines may increase the effects of Activelle®:

Medicines containing ketoconazole (a fungicide).

Activelle® may have an impact on a concomitant treatment

with cyclosporine.

Laboratory tests

If you need a blood test, tell your doctor or the laboratory staff

that you are taking Activelle®, because this medicine can affect

the results of some tests.

Taking Activelle® with food and drink

The tablets can be taken with or without food and drink.

Pregnancy and breast-feeding

Pregnancy: Activelle® is for use in postmenopausal women

only. If you become pregnant, stop taking Activelle® and

contact your doctor.

Breast-feeding: You should not take Activelle® if you are

breast-feeding.

Driving and using machines

Activelle® has no known effect on the ability to drive or use

machines.

Smoking

Do not use this medicine without consulting the doctor, in case

you are smoking. It is recommended to quit smoking while

using a hormonal combined preparation, such as Activelle®.

If you are unable to quit smoking and you are over 35 years,

consult your doctor.

Important information about some of the ingredients of

the medicine:

Activelle® contains lactose monohydrate. If you have an intolerance

to some sugars, contact your doctor before taking Activelle®.

3. How to use the medicine?

Always take this medicine exactly as your doctor has told you.

Check with your doctor or pharmacist if you are unsure. The dosage

and treatment regimen will be determind by the doctor only.

Take one tablet once a day, at about the same time each

day. Once you have finished all the 28 tablets in the pack, start

a new pack continuing the treatment without interruption.

For further information on the use of the calendar pack, see

‘User Instructions’ at the end of the package leaflet.

You may start treatment with Activelle® on any convenient

day. However, if you are switching from an HRT product when

you have monthly bleeding, start your treatment straight after

the bleeding has ended.

Your doctor will prescribe the lowest dose to treat your

symptom for as short as necessary. Speak to your doctor if you

think this dose is too strong or not strong enough.

There is no information regarding crushing/cutting, therefore,

it is not recommended.

If you accidentally took a higher dosage

If you have taken more Activelle® than you should, talk to

a doctor or pharmacist. An overdose of Activelle® could make

you feel sick or vomit.

If you forget to take the medicine

If you forget to take your tablet at the usual time, take it

within the next 12 hours. If more than 12 hours have gone by,

skip the missed dose and start again as normal the next day.

Do not take a double dose to make up for a forgotten tablet.

Forgetting a dose may increase the likelihood of breakthrough

bleeding and spotting if you still have your womb.

Adhere to the treatment as recommended by the doctor.

Do not stop the treatment without consulting your doctor,

even if there is an improvement in your health situation.

If you stop taking the medicine

If you would like to stop taking Activelle®, talk to your doctor

first. Your doctor will explain the effects of stopping treatment

and discuss other possibilities with you.

Do not take medicines in the dark! Check the label and the dose

each time

you take the medicine.

Wear glasses if you need them.

If you have any further questions on the use of this medicine,

ask your doctor or pharmacist.

If you need to have surgery

If you are going to have surgery, tell the surgeon that you are

taking Activelle®. You may need to stop taking Activelle® about

4 to 6 weeks before the operation to reduce the risk of a blood

clot (see section 2, ‘Blood clots in a vein (thrombosis)’). Ask

your doctor when you can start taking Activelle® again.

4. Side effects

As with any medicines, the use of Activelle® may cause side

effects in some users. Do not be alarmed when reading the list

of side effects. You may not suffer from any of them.

The following diseases are reported more often in women

using HRT compared to women not using HRT:

breast cancer

abnormal growth or cancer of the lining of the womb

(endometrial hyperplasia or cancer)

ovarian cancer

blood clots in the veins of the legs or lungs (venous

thromboembolism)

heart disease

stroke

memory loss if HRT is started over the age of 65.

For more information about these side effects, see section 2,

‘Before using the medicine’.

Hypersensitivity/allergy (uncommon side effect – affects

1 to 10 users in 1,000)

Though it is an uncommon event, hypersensitivity/allergy may

occur. Signs of hypersensitivity/allergy may include one or more

of the following symptoms: hives, itching, swelling, difficulty in

breathing, low blood pressure (paleness and coldness of skin,

rapid heart beat), feeling dizzy, sweating, which could be signs

of anaphylactic reaction/shock. If one of the mentioned

symptoms appears, stop taking Activelle® and seek

immediate medical help.

Very common side effects (affects more than 1 user in 10)

Breast pain or breast tenderness

Vaginal bleeding.

Common side effects (affects 1 to 10 users in 100)

Headache

Weight gain caused by fluid retention

Vaginal inflammation

Migraine, new or worse than before

Vaginal infection with a fungus

Depression, new or worse than before

Nausea

Enlargement or swelling of the breasts (breast oedema)

Back pain

Uterine fibroid (benign tumour), aggravation, occurrence

or reoccurrence

Swelling of arms and legs (peripheral oedema)

Weight increase.

Uncommon side effects (affects 1 to 10 users in 1,000)

Bloating, abdominal pain, swelling, discomfort or flatulence

Acne

Hair loss (alopecia)

Abnormal (male pattern) hair growth

Itching or hives (urticaria)

Inflammation of a vein (superficial thrombophlebitis)

Leg cramps

Drug ineffective

Allergic reaction

Nervousness.

Rare side effects (affects 1 to 10 users in 10,000)

Blood clots in the blood vessels of the legs or the lungs

(deep vein thrombosis, lung embolism).

Very rare side effects (affects less than 1 user in 10,000)

Cancer of the lining of the womb (endometrial cancer)

Excessive thickening of the lining of the womb

(endometrial hyperplasia)

Increase in blood pressure or worsening of high blood pressure

Gall bladder disease, gall stones occurrence/reoccurrence

or aggravated

Excessive secretion of sebum, skin eruption

Acute or recurring attack of oedema (angioneurotic oedema)

Insomnia, dizziness, anxiety

Change in sexual desire

Visual disturbances

Weight decreased

Vomiting

Heartburn

Vaginal and genital itching

Heart attack and stroke.

Other side effects of combined HRT

Gall bladder disease

Various skin disorders:

– discoloration of the skin especially of the face or neck

known as ‘pregnancy patches’ (chloasma)

– painful reddish skin nodules (erythema nodosum)

– rash with target-shaped reddening or sores (erythema

multiforme)

– red or purple discolorations of the skin and/or mucous

membranes (vascular purpura)

Reporting of side effects

If you get any side effects, including any possible side effects

not listed in this leaflet or if any of the side effects worsens

consult with the doctor. Reporting side effects to the ministery

of health is possible by clicking the link “report side effects of

drug treatment”, listed at the MoH website

(www.health.gov.il), which refers to a form intended for

reporting side effects or via the following link:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?

formType=AdversEffectMedic@moh.gov.il.

User Instructions

How to use the calendar pack

1. Set the day reminder

Turn the inner disc to set the day of the week opposite the

little plastic tab.

2. How to take the first day’s tablet

Break the plastic tab and tip out the first tablet.

3. Move the dial every day

On the next day, simply move the transparent dial clockwise

1 space as indicated by the arrow. Tip out the next tablet.

Remember to take only 1 tablet once a day.

You can only turn the transparent dial after the tablet in

the opening has been removed.

Activelle® is a trademark owned by

Novo Nordisk A/S.

© 2016

Novo Nordisk

5. How to store the medicine?

Avoid poisoning! This medicine, and any other medicine, must

be kept in a safe place out of the sight and reach of children

and/or infants in order to avoid poisoning.

Do not use this medicine after the expiry date, which is stated

on the label and outer carton after ‘EXP’.

The expiry date refers to the last day of that month.

Do not store above 25°C.

Do not refrigerate.

Keep the container in the outer carton in order to protect it

from light. Keep away from heat.

Do not throw away any medicines via wastewater or household

waste. Ask your pharmacist how to throw away medicines you

no longer use. These measures will help protect the environment.

6. Further information

In addition to the active substances, the medicine also

contains:

Lactose monohydrate, maize starch, copovidone, talc and

magnesium stearate.

The film-coating contains: hypromellose, glycerol triacetate and talc.

What Activelle® looks like and contents of the pack

The film-coated tablets are white, round with a diameter of 6 mm.

The tablets are engraved “NOVO 288” on one side and the

Novo Nordisk logo (an Apis bull) on the other side.

Pack sizes: 1×28 film-coated tablets in a calendar pack.

License holder

Novo Nordisk Ltd.

20 Hata’as St., Industrial Zone, Kfar Saba 4442520

Manufacturer name and address

Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark

This leaflet was checked and approved by the Ministry of

Health in June 2016.

Registration number of the medicine in the National Drug

Registry of the Ministry of Health: 114-30-29629-00

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ב רשואו קדבנ ונכותו תואירבה דרשמ י"ע עבקנ הז ןולע טמרופ ינוי

2016

1.

NAME OF THE MEDICINAL PRODUCT

Activelle® 1 mg/0.5 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains:

Estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 0.5 mg.

Excipient with known effect: lactose monohydrate.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablets.

White film-coated, round, biconvex tablets with a diameter of 6 mm. The tablets are engraved with

NOVO 288 on one side and the Apis bull on the other.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in women with more than 1 year

after menopause.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of or

contraindicated for other medicinal products approved for the prevention of osteoporosis.

The experience treating women older than 65 years is limited.

4.2

Posology and method of administration

Activelle is a continuous combined HRT product intended for use in women with an intact uterus.

One tablet should be taken orally once a day without interruption, preferably at the same time every day.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the

shortest duration (see also section 4.4) should be used.

A switch to a higher dose combination product could be indicated if the response after 3 months is

insufficient for symptom relief.

In women with amenorrhoea and not taking HRT or women in transition from another continuous combined

HRT product, treatment with Activelle may be started on any convenient day. In women in transition from a

sequential HRT regimen, treatment should start right after their withdrawal bleeding has ended.

If the patient has forgotten to take a tablet, the tablet should be taken as soon as possible within the next

12 hours. If more than 12 hours have passed, the tablet should be discarded. Forgetting a dose may increase

the likelihood of breakthrough bleeding and spotting.

4.3

Contraindications

Known, past or suspected breast cancer

Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)

Undiagnosed genital bleeding

Untreated endometrial hyperplasia

Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency (see section 4.4))

Active or previous arterial thromboembolic disease (e.g. angina, myocardial infarction)

Acute liver disease or a history of liver disease as long as liver function tests have failed to return to

normal

Known hypersensitivity to the active substances or to any of the excipients

Porphyria.

4.4

Special warnings and precautions for use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely

affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least

annually and HRT should only be continued as long as the benefit outweighs the risk.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due

to the low level of absolute risk in younger women, however, the balance of benefits and risks for these

women may be more favourable than in older women.

Medical examination/follow-up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken.

Physical (including pelvic and breast) examination should be guided by this and by the contraindications and

warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted

to the individual woman. Women should be advised what changes in their breasts should be reported to their

doctor or nurse (see ‘Breast cancer’ below). Investigations, including appropriate imaging tools, e.g.

mammography, should be carried out in accordance with currently accepted screening practices and

modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously and/or have been aggravated during

pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into

account that these conditions may recur or be aggravated during treatment with Activelle in particular:

Leiomyoma (uterine fibroids) or endometriosis

Risk factors for thromboembolic disorders (see below)

Risk factors for oestrogen dependent tumours, e.g. 1

degree heredity for breast cancer

Hypertension

Liver disorders (e.g. liver adenoma)

Diabetes mellitus with or without vascular involvement

Cholelithiasis

Migraine or (severe) headache

Systemic lupus erythematosus

A history of endometrial hyperplasia (see below)

Epilepsy

Asthma

Otosclerosis.

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in case a contraindication is discovered and in the following situations:

Jaundice or deterioration in liver function

Significant increase in blood pressure

New onset of migraine-type headache

Pregnancy.

Endometrial hyperplasia and carcinoma

In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when

oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk

among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending on the

duration of treatment and oestrogen dose (see section 4.8). After stopping treatment, the risk may remain

elevated for more than 10 years.

The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined

oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with

oestrogen-only HRT.

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding

or spotting continues after the first months of treatment, appears after some time during therapy, or continues

after treatment has been discontinued, the reason should be investigated, which may include endometrial

biopsy to exclude endometrial malignancy.

Breast cancer

The overall evidence suggests an increased risk of breast cancer in women taking combined oestrogen-

progestagen and possibly also oestrogen-only HRT that is dependent on the duration of taking HRT.

The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and epidemiological

studies are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-

progestagen HRT that becomes apparent after about 3 years (see section 4.8).

The excess risk becomes apparent within a few years of use, but returns to baseline within a few (at most 5)

years after stopping treatment.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic images

which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking

oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and

diminishes over time after stopping.

Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a

similar or slightly smaller risk (see section 4.8).

Venous thromboembolism

HRT is associated with a 1.3 to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein

thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT

than later (see section 4.8).

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT

is therefore contraindicated in these patients (see section 4.3).

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery, prolonged

immobilisation, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus

(SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following

surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT 4 to 6 weeks

earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a

young age, screening may be offered after careful counselling regarding its limitations (only a proportion of

thrombophilic defects are identified by screening).

If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is

‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is

contraindicated.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of

HRT.

If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact

their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful

swelling of a leg, sudden pain in the chest, dyspnoea).

Smoking

This product should not be prescribed to a woman who is a smoker, espcially if she is older than 35, without

careful medical evaluation.

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women

with or without existing CAD who received combined oestrogen-progestagen or oestrogen-only HRT.

The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As the

baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to

oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with more

advanced age.

Ischaemic stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase

in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as

the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will

increase with age (see section 4.8).

Other conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be

carefully observed.

Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or

hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to

pancreatitis have been reported with oestrogen therapy in this condition.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone,

as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by

radioimmunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3

concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin

(CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex

steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma

proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin and ceruloplasmin).

HRT use does not improve cognitive function. There is some evidence of increased risk of probable

dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

Activelle contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the

Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens and progestagens may be increased by concomitant use of substances known

to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g.

phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine,

efavirenz).

Ritonavir, telaprevir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing

properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s Wort

(Hypericum perforatum) may induce the metabolism of oestrogens and progestagens.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and

changes in the uterine bleeding profile.

Drugs that inhibit the activity of hepatic microsomal drug metabolising enzymes, e.g. ketoconazole, may

increase circulating levels of the active substances in Activelle.

Concomitant administration of cyclosporine and Activelle may cause increased blood levels of cyclosporine,

creatinine and transaminases due to decreased metabolism of cyclosporine in the liver.

4.6

Fertility, pregnancy and lactation

Pregnancy

Activelle is not indicated during pregnancy.

If pregnancy occurs during medication with Activelle, treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the

foetus. At doses higher than those normally used in OC and HRT formulations, masculinisation of female

foetuses was observed.

The results of most epidemiological studies to date, relevant to inadvertent foetal exposure to combinations

of oestrogens and progestagens, indicate no teratogenic or foetotoxic effect.

Lactation

Activelle is not indicated during lactation.

Fertility

No data available.

4.7

Effects on ability to drive and use machines

Activelle has no known effect on the ability to drive or use machines.

4.8

Undesirable effects

Clinical experience

The most frequently reported adverse events in the clinical trials with Activelle were vaginal bleeding and

breast pain/tenderness, reported in approximately 10% to 20% of patients. Vaginal bleeding usually occurred

in the first months of treatment. Breast pain usually disappeared after a few months of therapy. All adverse

events observed in the randomised clinical trials with a higher frequency in patients treated with Activelle as

compared to placebo, and which on an overall judgement are possibly related to treatment, are presented in

the table below.

System organ class

Very common

≥ 1/10

Common

≥ 1/100; < 1/10

Uncommon

≥ 1/1,000; < 1/100

Rare

≥ 1/10,000;

< 1/1,000

Infections and

infestations

Genital candidiasis

or vaginitis, see

also ‘Reproductive

system and breast

disorders’

Immune system

disorders

Hypersensitivity,

see also ‘Skin and

subcutaneous

tissue disorders’

Metabolism and

nutrition disorders

Fluid retention, see

also ‘General

disorders and

administration site

conditions’

Psychiatric disorders

Depression or

depression

aggravated

Nervousness

Nervous system

disorders

Headache,

migraine or

migraine

aggravated

Vascular disorders

Thrombophlebitis

superficial

Deep venous

thromboembolism

Pulmonary embolism

Gastrointestinal

disorders

Nausea

Abdominal pain,

abdominal

distension or

abdominal

discomfort

Flatulence or

bloating

Skin and

Alopecia, hirsutism

subcutaneous tissue

disorders

or acne

Pruritus or urticaria

Musculoskeletal and

connective tissue

disorders

Back pain

Leg cramps

Reproductive system

and breast disorders

Breast pain or

breast

tenderness

Vaginal

haemorrhage

Breast oedema or

breast enlargement

Uterine fibroids

aggravated or

uterine fibroids

reoccurrence or

uterine fibroids

General disorders

and administration

site conditions

Oedema peripheral

Drug ineffective

Investigations

Weight increased

Post-marketing experience

In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously

reported, and are by an overall judgement considered possibly related to Activelle treatment. The reporting

rate of these spontaneous adverse drug reactions is very rare (< 1/10,000, not known (cannot be estimated

from the available data)). Post-marketing experience is subject to underreporting especially with regard to

trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light:

Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer

Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic reaction/shock)

Psychiatric disorders: Insomnia, anxiety, libido decreased, libido increased

Nervous system disorders: Dizziness, stroke

Eye disorders: Visual disturbances

Cardiac disorders: Myocardial infarction

Vascular disorders: Hypertension aggravated

Gastrointestinal disorders: Dyspepsia, vomiting

Hepatobiliary disorders: Gallbladder disease, cholelithiasis, cholelithiasis aggravated, cholelithiasis

recurrence

Skin and subcutaneous tissue disorders: Seborrhoea, rash, angioneurotic oedema

Reproductive system and breast disorders: Endometrial hyperplasia, vulvovaginal pruritus

Investigations: Weight decreased, blood pressure increased.

Other adverse reactions have been reported in association with oestrogen/progestagen treatment:

Skin and subcutaneous disorders: Alopecia, chloasma, erythema multiforme, erythema nodosum,

vascular purpura

Probable dementia over the age of 65 (see section 4.4).

Breast cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined

oestrogen-progestagen therapy for more than 5 years.

Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of

oestrogen-progestagen combinations.

The level of risk is dependent on the duration of use (see section 4.4).

Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study

(MWS) are presented below:

Million Women Study – Estimated additional risk of breast cancer after 5 years’ use

Age range (years)

Incidence per 1,000

never-users of HRT

over 5 years*

Risk ratio**

Additional cases per

1,000 HRT users over

5 years’ use (95% CI)

Oestrogen-only HRT

50-65

9-12

1-2 (0-3)

Combined oestrogen-progestagen

50-65

9-12

6 (5-7)

* Taken from baseline incidence rates in developed countries.

** Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will

also change proportionately.

US WHI Studies – Additional risk of breast cancer after 5 years’ use

Age range (years)

Incidence per 1,000

women in placebo

arm over 5 years

Risk ratio and

95% CI

Additional cases per

1,000 HRT users over

5 years’ use (95% CI)

CEE oestrogen-only

50-79

0.8 (0.7-1.0)

-4 (-6-0)*

CEE+MPA oestrogen-progestagen**

50-79

1.2 (1.0-1.5)

4 (0-9)

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

** When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during

the first 5 years of treatment. After 5 years the risk was higher than in non-users.

Endometrial cancer risk

The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of

endometrial cancer (see section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial

cancer in epidemiological studies varied from between 5 and 55 extra cases diagnosed in every 1,000 women

between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk.

In the Million Women Study, the use of 5 years of combined (sequential or continuous) HRT did not

increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer risk

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly increased

risk of having ovarian cancer diagnosed (see section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women

currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). For

women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2,000 users. In

women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be diagnosed with ovarian

cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3- to 3-fold increased relative risk of developing venous thromboembolism

(VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in

the first year of using HRT (see section 4.4). Results of the WHI studies are presented below:

WHI Studies – Additional risk of VTE over 5 years’ use

Age range (years)

Incidence per 1,000

women in placebo

arm over 5 years

Risk ratio and

95% CI

Additional cases per

1,000 HRT users over

5 years’ use (95% CI)

Oral oestrogen-only*

50-59

1.2 (0.6-2.4)

1 (-3-10)

Oral combined oestrogen-progestagen

50-59

2.3 (1.2-4.3)

5 (1-13)

* Study in women with no uterus.

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT

over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5-fold increased

relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.

This relative risk is not dependent on age or on duration of use, but the baseline risk is strongly age-

dependent. The overall risk of stroke in women who use HRT will increase with age (see section 4.4).

WHI Studies Combined – Additional risk of ischaemic stroke* over 5 years’ use

Age range (years)

Incidence per 1,000

women in placebo

arm over 5 years

Risk ratio and

95% CI

Additional cases per

1,000 HRT users over

5 years’ use (95% CI)

50-59

1.3 (1.1-1.6)

3 (1-5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.gov.il).

4.9

Overdose

Overdose may be manifested by nausea and vomiting. Treatment should be symptomatic.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Progestagens and oestrogens, fixed combinations, ATC code: G03FA01.

Mechanism of action

Estradiol: The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to

endogenous human estradiol. It substitutes for the loss of oestrogen production in postmenopausal women,

and alleviates menopausal symptoms.

Oestrogens prevent bone loss following menopause or ovariectomy.

Norethisterone acetate: Synthetic progestagen with actions similar to those of progesterone, a natural female

sex hormone. As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk

of endometrial hyperplasia and cancer. The addition of a progestagen reduces the oestrogen-induced risk of

endometrial hyperplasia in non-hysterectomised women.

Pharmacodynamic effects

In clinical trials with Activelle, the addition of the norethisterone acetate component enhanced the vasomotor

symptom relieving effect of 17β-estradiol.

Relief of menopausal symptoms is achieved during the first few weeks of treatment.

Activelle is a continuous combined HRT given with the intent of avoiding the regular withdrawal bleeding

associated with cyclic or sequential HRT. Amenorrhoea (no bleeding or spotting) was seen in 90% of the

women during months 9-12 of treatment. Bleeding and/or spotting was observed in 27% of the women

during the first 3 months of treatment and in 10% during months 10-12 of treatment.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass.

The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for

as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in

untreated women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in

combination with a progestagen – given to predominantly healthy women – reduces the risk of hip, vertebral

and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or

established osteoporosis, but the evidence for that is limited.

The effects of Activelle on bone mineral density were examined in 2 two-year, randomised, double-blind,

placebo-controlled clinical trials in postmenopausal women (n=327 in one trial, including 47 on Activelle

and 48 on Kliogest (2 mg estradiol and 1 mg norethisterone acetate); and n=135 in the other trial, including

46 on Activelle). All women received calcium supplementation ranging from 500 to 1,000 mg daily.

Activelle significantly prevented bone loss at the lumbar spine, total hip, distal radius and total body in

comparison with calcium supplemented placebo-treated women. In early postmenopausal women (1 to 5

years since last menses), the percentage change from baseline in bone mineral density at lumbar spine,

femoral neck and femoral trochanter in patients completing 2 years of treatment with Activelle was

4.8+0.6%, 1.6+0.7% and 4.3+0.7% (mean + SEM), respectively, while with the higher dose combination

containing 2 mg E

and 1 mg NETA (Kliogest) it was 5.4+0.7%, 2.9+0.8% and 5.0+0.9%, respectively. The

percentage of women who maintained or gained bone mineral density during treatment with Activelle and

Kliogest was 87% and 91%, respectively, after 2 years of treatment. In a study conducted in postmenopausal

women with a mean age of 58 years, treatment with Activelle for 2 years increased the bone mineral density

at lumbar spine by 5.9+0.9%, at total hip by 4.2+1.0%, at distal radius by 2.1

0.6%, and at total body by

3.7+0.6%.

5.2

Pharmacokinetic properties

Absorption and distribution of 17β-estradiol

Following oral administration of 17β-estradiol in micronised form, rapid absorption from the gastrointestinal

tract occurs. It undergoes extensive first-pass metabolism in the liver and other enteric organs, and reaches a

peak plasma concentration of approximately 35 pg/ml (range 21-52 pg/ml) within 5-8 hours. The half-life of

17β-estradiol is about 12-14 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only

approximately 1-2% is unbound.

Biotransformation and elimination of 17β-estradiol

Metabolism of 17β-estradiol, occurs mainly in the liver and the gut but also in target organs, and involves the

formation of less active or inactive metabolites, including oestrone, catecholoestrogens and several oestrogen

sulfates and glucuronides. Oestrogens are excreted with the bile, hydrolysed and reabsorbed (enterohepatic

circulation), and mainly eliminated in urine in biologically inactive form.

Absorption and distribution of norethisterone acetate

After oral administration, norethisterone acetate is rapidly absorbed and transformed to norethisterone

(NET). It undergoes first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma

concentration of approximately 3.9 ng/ml (range 1.4-6.8 ng/ml) within 0.5-1.5 hours. The terminal half-life

of NET is about 8-11 hours. NET binds to SHBG (36%) and to albumin (61%).

Biotransformation and elimination of norethisterone acetate

The most important metabolites are isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted

mainly in the urine as sulfate or glucuronide conjugates.

The pharmacokinetic properties in the elderly have not been studied.

5.3

Preclinical safety data

The acute toxicity of oestrogens is low. Because of marked differences between animal species and between

animals and humans, preclinical results possess a limited predictive value for the application of oestrogens in

humans.

In experimental animals, estradiol or estradiol valerate displayed an embryolethal effect already at relatively

low doses; malformations of the urogenital tract and feminisation of male foetuses were observed.

Norethisterone, like other progestagens, caused virilisation of female foetuses in rats and monkeys. After

high doses of norethisterone, embryolethal effects were observed.

Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic

potential revealed no particular human risks beyond those discussed in other sections of the SPC.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core:

Lactose monohydrate

Maize starch

Copovidone

Talc

Magnesium stearate

Film-coating:

Hypromellose

Glycerol triacetate

Talc

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

Do not store above 25

C. Do not refrigerate. Keep the container in the outer carton in order to protect it from

light. Protect from heat.

6.5

Nature and contents of container

1 x 28 tablets or 3 x 28 tablets in calendar dial packs.

The calendar dial pack with 28 tablets consists of the following 3 parts:

The base made of coloured non-transparent polypropylene.

The ring-shaped lid made of transparent polystyrene.

The centre-dial made of coloured non-transparent polystyrene.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. Registration number:

Activelle®:

114-30-29629-00

8. Manufacturer:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

9. Marketing Authorisation Holder:

Novo Nordisk Ltd.

20 HaTa’as St. Indust. Area,

Kfar Saba, 4442520

The content of this leaflet was checked and approved by the Ministry of Health in June 2016.